Bone regeneration and stem cells

Abstract

This invited review covers research areas of central importance for orthopaedic and maxillofacial bone tissue repair, including normal fracture healing and healing problems, biomaterial scaffolds for tissue engineering, mesenchymal and foetal stem cells, effects of sex steroids on mesenchymal stem cells, use of platelet-rich plasma for tissue repair, osteogenesis and its molecular markers. A variety of cells in addition to stem cells, as well as advances in materials science to meet specific requirements for bone and soft tissue regeneration by addition of bioactive molecules, are discussed.

Fig 1

Molecular structure of (A) PLA and (B) PLC.

Fig 2

Molecular structure of poly(propylene fumarate).

Fig 3

Molecular structure of poly(1,5-dioxepan-2-one) (DXO).

Fig 4

Development stage, cell type and source of cells currently used in cellular therapy. Cellular source can come from human and animals at different stages of development including embryonic, embryonic-foetal, foetal and adult involving different beginning tissue sources ranging from zygotes to specific tissues (bone marrow, adipose, amniotic fluid, skin, liver, bone, cartilage etc.). Embryonic stem cells are derived from embryos at early stage where less than 100 cells are present, followed by foetal stem cells that are taken from the genital ridge section from 5 to 8 weeks of gestation (drawing modified from http://commons.wikimedia.org/wiki/Image:10_weeks_pregnant.jpg donated by wouter.vengeer@tribal.nl with a free license). Tissue-specific foetal cells are taken following 9 weeks of gestation usually up to 14–16 weeks from normal tissue. Adult stem cells can be isolated from most tissue sources but are rare with only 1 in every 10⁴ to 10⁵ of total cell volume.

Fig 5

Organization of a cell therapy platform. Director of technical and logistics coordinates the program with essential legal and ethical advisors and a medical director for interpretation of medical quality assurance (serology and pathology reports). The separation of hospitals for the organ donation and all other aspects of the platform including serology, pathology and the GLP cell culture laboratory can assure complete anonymous and coded organ donations. Importantly, the Director of Technical and Logistics is not involved in any manner in the organ donation process as required by law. Final approval for use of validated cell banks for human therapy is coordinated and approved with both Hospital Ethics Committees and National regulatory agencies (i.e. European Medicines Association, Food and Drug Administration, SwissMedic [32]).

Fig 6

Schematic representation of the principal signalling networks and transcription factors regulating osteoblast differentiation and osteogenesis (see text for details). Lines with arrowheads indicate a positive action, lines with bars indicate an inhibition and dashed lines indicate that function has to be proven. The lineage commitment and the differentiation of cultured MSC are signed by the acquisition of specific osteoblast functions. In boxes are shown genes that are significantly up-regulated during osteogenic differentiation of MSC. The ‘Gene Ontology Annotation’ of genes listed here is associated to GF-signalling pathways, cell communication and skeletal development. The up-regulated genes have been grouped according to the differentiation status of cultured MSC: ‘Pre-osteoblasts’ are MSC which are able to produce ALP (cytochemical activity, ×10) and generate ‘Colony Forming Units’; ‘Differentiated osteoblasts’ are cells which have the competence to deposit mineral nodules in vitro (von Kossa staining, ×10). Genes are reported with the official symbol, as shown in ‘Gene’ database (http://www.ncbi.nlm.nih.gov/sites/entrez?db=gene).